The present invention relates generally to a process for the production of alkanoic acids, and particularly to a process for the production of lower alkanoic acids by acid catalyzed hydrolysis and decarboxylation of substituted malonic esters without the use of solvents.
Many lower alkanoic acids are known to be useful for their pharmacological properties, as pharmacological intermediates and as chemical intermediates. A particularly important lower alkanoic acid is valproic acid, (CH.sub.3 CH.sub.2 CH.sub.2).sub.2 CHCOOH, which is widely used in the pharmaceutical industry for its anticonvulsant and antiepileptic properties.
A well-known process for preparing alkanoic acids involves the hydrolysis and decarboxylation of malonic esters. The malonic ester is saponified with aqueous sodium hydroxide to form an aqueous solution of the disodium salt and ethanol. The salt solution is treated with a strong mineral acid to produce a mineral acid sodium salt and to precipitate the solid dicarboxylic acid. The dicarboxylic acid is isolated from the solution by conventional separation procedures, such as filtration or extraction, and the sodium salt is discarded as waste. The isolated acid is dried and heated to a temperature sufficient to cause decarboxylation to occur. This procedure is lengthy, requires numerous steps, generates waste, and is equipment intensive.
Acid catalyzed hydrolysis of carboxylic esters has certain advantages over the classical procedure described above. For example, the production of the intermediate sodium salt and the resultant generation of waste material is avoided. The dicarboxylic acid isolation step is eliminated and, in some instances, the acid catalyst may be recovered for reuse. Nonetheless, certain problems persist in the known acid hydrolysis procedures. For example, the rate of the reaction is slow, and it is often difficult to drive the hydrolysis to completion due to the competing reverse reaction of esterification. Additionally, many of these procedures are equipment intensive and require substantial excesses of some of the ingredients.
Several methods have been described in the literature as attempts to overcome the difficulties encountered in the acid hydrolysis procedures. For example, German Patent 30 45 102 discloses a gas phase reaction for the production of substituted acetic acids and/or their esters. Only partial conversion of the acid is accomplished by this method, and severe conditions are required for the reaction.
Another process utilizing acid hydrolysis was disclosed by B. Loev in Chemistry and Industry, (London), 1964, p. 193. This reference teaches acid catalyzed hydrolysis of esters using large amounts of acetic or formic acid as a solvent in the presence of 100 mole % of a mineral acid, such as methanesulfonic acid. In order to recover the carboxylic acid product, it is necessary to isolate the product from the reaction mixture by filtration or extraction, or by heating to remove the volatile materials, and thereafter recrystallizing or distilling the residue. The mineral acid may not normally be reclaimed from the solvent for reuse in this procedure, and halogenated hydrocarbon by-products are generated as waste when the mineral acid is hydrochloric or hydrobromic acid.
Landini and Rolla, J. Org. Chem., 1982, Vol. 47, p. 154-157, disclose a process for acid hydrolysis of carboxylic esters in a two-phase system in the presence of catalytic amounts of a quaternary onium salt. This hydrolysis proceeds at room temperature in the presence of a large excess of a strong mineral acid, such as hydrobromic acid, sulfuric acid or hydrochloric acid. Disadvantages of this process are that a two-phase system is required, and that the reaction must proceed in the presence of the large excess of the mineral acid. Halogenated hydrocarbons are also produced as by-products by this process when hydrobromic and hydrochloric acids are used.
Vogel, Textbook of Practical Organic Chemistry, Fourth Ed., Longman Group Limited (1978), p. 194-5, teaches a method for acid hydrolysis of some highly oxygenated malonic esters by refluxing with a large molar excess of aqueous hydrochloric acid. The ethanol generated by the reaction is removed by distillation as fast as it is formed, without undue removal of water, in order to drive the hydrolysis reaction to completion. Since the esters utilized in this process are highly oxygenated, these esters are soluble in hot water, and the intermediate dicarboxylic acids are decarboxylated at 100.degree. C. The carboxylic acid is recovered by evaporating the solution to dryness under reduced pressure, redissolving in water, and again evaporating to dryness to remove the excess hydrochloric acid. The residue is thereafter dissolved in water, passed through a column of decolorizing carbon, and again evaporated to dryness under reduced pressure. The dried residue is ground to a fine powder, mixed with ether, filtered, washed with ether and dried. This process is lengthy and equipment intensive, requires the use of a large molar excess of strong acid solvent, and cannot be used with hydrophobic starting esters.
Another method for preparing valproic acid is disclosed in Polish Patent 136,499.Dipropylmalonic acid is decarboxylated by heating at 140.degree.-145.degree. C. in the presence of 2 wt % valproic acid, the valproic acid acting as a decarboxylation catalyst. In this process, the diacid must be prepared and isolated by the classical method prior to the decarboxylation.
U.S. Pat. No. 5,101,070 discloses a process for producing valproic acid from an acetoacetic acid ester by a three-step process. The first step involves producing a 2,2-dipropyl acetoacetic acid ester from an acetoacetic acid ester in the presence of a basic catalyst. In the second step the 2,2-dipropyl acetoacetic acid ester is deacetylated with an alcohol in the presence of a basic catalyst to give a valproic acid ester. The third step involves hydrolyzing the valproic acid ester. In the hydrolysis step, the valproic acid ester is heated under reflux at elevated temperatures for 2-5 hours. The pH of the reaction solution is adjusted to 9 to 10, and the solution is extracted with an organic solvent. The pH of the aqueous layer is adjusted to about 2, and the organic layer containing the valproic acid is separated. This process is lengthy and generates waste as a result of the neutralization step.
U.S. Pat. No. 3,661,950 discloses a process for producing alkanoic acids having between 1 and 20 carbon atoms from nitroketones. A vicinal nitroketone is contacted under nonaqueous conditions with a catalyst comprising a sulfonic acid cation exchange resin. The alkanoic acid is recovered by separating the catalyst, and then cooling the reaction mixture to a temperature below 100.degree. C. The solid catalyst is recovered by filtration. The alkanoic acid and hydrocarbons are thereafter separated by distillation. The use of nitro compounds of the type utilized in this process can be hazardous due to the generally higher toxicity of these compounds when compared to alkanes. Also, the nitro compounds are more unstable than conventional reactants used for producing alkanoic acids. Since fractional distillation is required for the separation, it is also expected that the purity of the final product would be lower than desired.
The known processes for the production of lower alkanoic acids, such as valproic acid, generally require either expensive starting ingredients, lengthy and time consuming procedures and/or a wide array of laboratory equipment in order to perform the process. They also generate waste in the form of by-products and frequently require large excesses of reaction ingredients. Some of the processes are not effective when hydrophobic starting materials are hydrolyzed.
Accordingly, it is desired to provide a process for the production of lower alkanoic acids that is cost effective, provides a satisfactory yield of product, does not generate a significant amount of solid waste, and enables the alkanoic acid product to be produced in one reactor in an uninterrupted operation.